Novel Vaccine against Pathological Pyroglutamate-Modified Amyloid Beta for Prevention of Alzheimer’s Disease

Post-translationally modified N-terminally truncated amyloid beta peptide with a cyclized form of glutamate at position 3 (pE(3)Aβ) is a highly pathogenic molecule with increased neurotoxicity and propensity for aggregation. In the brains of Alzheimer’s Disease (AD) cases, pE(3)Aβ represents a major constituent of the amyloid plaque. The data show that pE(3)Aβ formation is increased at early pre-symptomatic disease stages, while tau phosphorylation and aggregation mostly occur at later stages of the disease. This suggests that pE(3)Aβ accumulation may be an early event in the disease pathogenesis and can be prophylactically targeted to prevent the onset of AD. The vaccine (AV-1986R/A) was generated by chemically conjugating the pE(3)Aβ(3-11) fragment to our universal immunogenic vaccine platform MultiTEP, then formulated in Advax(CpG) adjuvant. AV-1986R/A showed high immunogenicity and selectivity, with endpoint titers in the range of 10(5)–10(6) against pE(3)Aβ and 10(3)–10(4) against the full-sized peptide in the 5XFAD AD mouse model. The vaccination showed efficient clearance of the pathology, including non-pyroglutamate-modified plaques, from the mice brains. AV-1986R/A is a novel promising candidate for the immunoprevention of AD. It is the first late preclinical candidate which selectively targets a pathology-specific form of amyloid with minimal immunoreactivity against the full-size peptide. Successful translation into clinic may offer a new avenue for the prevention of AD via vaccination of cognitively unimpaired individuals at risk of disease.